1. Field of the Invention
The invention relates to systems and methods for producing capsules and particles with at least one encapsulated and/or entrapped agent, such as therapeutic agent, imaging agents, and other constituents. More particularly, the agent encapsulated in a vehicle, capsule, particle, vector, or carrier may maximize treatment and/or imaging of malignancy while minimizing the adverse effects of treatment and/or imaging.
2. Related Art
Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis. Cancer may affect people at all ages, but risk tends to increase with age. It is one of the principal causes of death in developed countries.
For example, according to the National Cancer Institute, breast cancer affected between 12 and 13 per every 10,000 women in 2003. Although imaging and early diagnostic tools have been improving over the past two decades, current breast cancer early detection is far from infallible, especially when using mammograms in younger women. While magnetic resonance imaging (MRI and ultrasound) and laser-based imaging techniques have been used or evaluated, the issue for best-possible contrast between healthy and cancerous tissue for any imagining technique is a longstanding one.
A current challenge facing scientists is determining how to design a therapeutic or an imaging agent and its vehicle, vector or carrier in order to maximize treatment and imaging of malignant cancers in patients while minimizing the adverse effects of treatment. Moreover, the selective delivery of therapeutic agents to a desired part of the body is also a nontrivial issue. Current treatments may lead to insufficient tumor distribution or therapeutic agents and often cause adverse effects on patients. Systemic injections of therapeutic agents carry consequences associated with their nonspecific dispersion in the body and have a limited therapeutic agent distribution throughout the targeted malignancy. One approach to overcome these short comings is to design an effective therapeutic or imaging agent delivery vehicle by making vesicles or capsules containing the desired therapeutic agent.
Formation of vesicles or capsules that are small enough to be delivered into the human body by means of inhalation, injection or permeation through the skin has received significant attention. The outer skin or shell of the vesicles may be chemically functionalized with receptors and other species to selectively target certain organs. There are several methodologies available, such as electrospray and two-capillary jet systems to fabricate small vesicles.
Emulsion-polymerization technologies, such as DC coaxial electrospray, AC coaxial electrospray, and electrohydrodynamics (EHD) are well known methods that may produce micron-sized capsules. In general, a solution containing the target compound or compounds to be encapsulated, also called “encapsulates,” is emulsified into another fluid to solution having at least one substance capable of forming a shell or envelope around the encapsulate dispersed droplets. Although emulsion-polymerization methods are relatively scalable, there are several limitations associated with the methods, such as the inability to encapsulate the targets in a quantitative manner, and the high-shear production of emulsions may compromise the integrity of mechanically delicate encapsulates, such as biological constituents such as proteins, genetic material, and other molecules of biological origin.
Coaxial electrospray based on application of DC electrical potentials between a coaxial capillary fixture delivering the encapsulate-containing core liquid and a shell-forming liquid precursor, and a collector surface or counter-electrode, has the ability to produce vesicles in the micrometer and sub-micrometer range. Although DC coaxial electrospray may be relatively gentle to biological encapsulates, its major limitation is that it lacks simplicity in equipment, design, scalability, and thus cost effectiveness.
As an alternative to DC based electrospray, AC electrospray may be employed. For example, AC electrospray may be used to produce encapsulates entrapped within a bioabsorbable biopolymeric matrix, such as polylactic acid. AC electrospray yields essentially an electrically neutral electrospray. While there are advantages associated with charge neutrality, such as decreased ability of the particles or electrospray droplets to absorb indiscriminately over non-targeted surfaces, and avoidance of a potential charge buildup problem. One disadvantage of AC electrospray is that it produces undesirablely large particles having sizes well above one micron. For many medical applications, such as penetration of the blood brain barrier, AC electrospray derived particles are unacceptably large.
In addition to electrospray methodologies, coaxial liquid jet system combined with sol-gel chemistry, such as EHD, may be employed to fabricate vesicles or capsules. Use of coaxial, two-capillary coaxial arrangements to simultaneously deliver two fluids in the presence of electric field gradients are well known in the art.
Briefly, in this method, the chemistry and physical properties of the two fluids and the values of variables such as electric field strength and flow rates of the two fluids may determine the structure of matter collected onto a collector electrode, which may be located at a distance from the exit region of the two-capillary coaxial arrangement. At the exit region, the compound two-fluid structure may form an electrified meniscus that may adopt various shapes, such as a Taylor cone.
FIG. 1, which illustrates a fluid flow generated by a two-coaxial capillary system of the prior art, depicts a two-fluid stream 100 in the presence of electric field gradients, where the internal fluid 104 is enveloped by the external fluid 106. The quasi-conical Taylor cone structure 108 issues an electrified compound two-fluid jet from its apex 110. here, the electrified liquid jet experiences thinning due to same-charge repulsion effects. Moreover, the thinning of the jet may be a function of the physical properties of the two liquids such as, dielectric constants, viscosities, conductivities and surface tensions. Although differentiated two-fluid structures may occur when fluid 104 and fluid 106 do not mix, they may also occur when fluid 104 and fluid 106 are miscible or partially miscible, because both fluids flow under the so-called laminar flow regime.
Laminar flows may be non-turbulent, which may minimize mixing between flowing fluid layers. Thus, since the two fluids may not mix to the point of forming a single fluid phase, the thinning electrified two-fluid jet may enter into a chaotic path resembling whipping phenomena. At a point along its path toward a collection zone or collector body 112, the compound two-fluid jet may experience an electrical charge oscillatory phenomenon known as Rayleigh instability. This may cause the compound two-fluid jet to no longer experience progressive thinning, but an oscillatory thinning and thickening regime which may eventually lead to jet breakup into a droplet-in-droplet regime, or compound electrospray regime.
The chemical and physical properties of the two fluids may be controlled to produce a variety of structures collected at the collection zone or collector electrode 112. For example, if fluid 106 yields a solid structure through solvent evaporation and precipitation of a solid phase, fluid 104 may be encapsulated into structures such as hollw fibers, hollow beaded fibers or capsules, for example. Alternatively, the chemical and physical properties of the two liquids may be adjusted to cause no solidification of fluid 104 and fluid 106, solidification of one of the two fluids, or solidification of both fluids, during the time of travel of the compound charged structures from the two-fluid electrified meniscus to the collection zone 112.
Referring to FIG. 1, regions 3, 4, and 5 are shown. If certain physiochemical phenomena lead to solidification of fluid 106 in region 3, tubular structures encapsulating fluid 104 inside a solid shell formed from fluid 106 may be obtained. If, however, solidification phenomena in fluid 106 occur in region 4, hollow beaded fibers with encapsulated fluid 104 may be obtained. Alternatively, if solidification phenomena in fluid 106 occur in region 5, capsules with encapsulated fluid 104 may be obtained. Wetted fibers, wetted beaded fibers or wetted particles may result in regions 3, 4, and 5, respectively, in cases where fluid 104 solidifies but fluid 106 does not. Core-shell solid structures may result when both fluids solidify prior to reaching the collection zone.
Although coaxial two-capillary systems may be employed to produce the core-shell structures, described above, there are several disadvantages associated with the conventional systems. In particular, when a direct, parallel scale-up of the process to increase process throughput is attempted a micro-fabrication problem occurs. For instance, a typical range of internal diameters for the inner and outer capillaries are about 0.1 to about 0.3 mm and about 0.3 to about 1.0 mm, respectively, In order to build an instrument consisting of many such coaxial, two-capillary fixtures for scaled up production of a desired core-shell structure, it is necessary to produce each individual fixture with inner and outer capillaries aligned as close to coaxial as possible, and also with high reproducibility in their diameters. With modern micro-fabrication techniques such challenge may be met, however, these techniques are very complex and not cost effective.
In particular, a conventional way to manage fluid flow through many orifices, capillaries, conduits or two-capillary coaxial fixtures is by using one means for forcing flow through all same fluid orifices, capillaries, conduits or two-capillary coaxial fixtures, not by controlling the fluid flow rate through each individual fluid flow path. This is the reason why, for example, fabricating a parallel scaled up production of a desired core-shell structure is difficult and expensive. If there is variability in diameter from inner or outer capillary of one two-capillary coaxial fixture to another in excess of about 2% or 3%, it is not possible to produce a desired core-shell structure without the occurrence of undesirable structures. With such prior art two-capillary fixture, small differences in the overall pressure drop profiles of the inner and outer capillaries also causes undesirable effects.